A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics
Levodopa is the gold standard treatment for Parkinson’s disease. However, a high unmet medical need exists for longer-lasting oral levodopa formulations to achieve sustained motor improvement with reduced risk of the effect wearing off. In our previous non-clinical studies using rats, more than 3-fo...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1596139/full |
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| author | Akane Hayashi Atsushi Hosomi Shinsaku Kihara Masato Nishi Saori Torisawa Yoshiumi Ouchi Hidenori Takada Junichi Enokizono |
| author_facet | Akane Hayashi Atsushi Hosomi Shinsaku Kihara Masato Nishi Saori Torisawa Yoshiumi Ouchi Hidenori Takada Junichi Enokizono |
| author_sort | Akane Hayashi |
| collection | DOAJ |
| description | Levodopa is the gold standard treatment for Parkinson’s disease. However, a high unmet medical need exists for longer-lasting oral levodopa formulations to achieve sustained motor improvement with reduced risk of the effect wearing off. In our previous non-clinical studies using rats, more than 3-fold prolongation of the levodopa half-life was achieved when it was combined with a high carbidopa dose. This study aimed to evaluate the effects of high-dose carbidopa on the pharmacokinetics of levodopa. A phase I study was performed to examine the effects of a combination of levodopa, carbidopa, and entacapone in healthy male volunteers. Levodopa and entacapone doses were set at approved dose levels. The carbidopa dose ranged from the approved 10 mg–600 mg. In addition to plasma concentrations of levodopa, those of the metabolites were also determined to evaluate their inhibitory effects on levodopa-metabolizing enzymes. The plasma concentrations of levodopa and its metabolites were monitored by liquid chromatography-tandem mass spectrometry up to 24 h after administration. The observed adverse effects were mild, and all participants completed the study. At higher carbidopa doses, the area under the levodopa plasma concentration-time curve increased by approximately 2-fold, and the half-life of levodopa was slightly prolonged by < 1.4-fold. These changes were much smaller than those observed in rats. The ratios of levodopa metabolites suggested that dopa deoxycarboxylase inhibition was saturated at a carbidopa dose of 300 mg. In conclusion, higher carbidopa doses are tolerable, and the effect of carbidopa on levodopa half-life is limited.Clinical trial registrationhttps://jrct.mhlw.go.jp/en-latest-detail/jRCT2051200104, registry number jRCT2051200104. |
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| institution | Matheson Library |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-beefd21a788648cd8b2dcebcd33c6ebd2025-07-07T08:11:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.15961391596139A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokineticsAkane Hayashi0Atsushi Hosomi1Shinsaku Kihara2Masato Nishi3Saori Torisawa4Yoshiumi Ouchi5Hidenori Takada6Junichi Enokizono7Research Management Office, Research Planning Department, Research Division, Kyowa Kirin Co., Ltd., Tokyo, JapanPharmacokinetics Research Laboratories, Research Unit, Research Division, Kyowa Kirin Co., Ltd., Shizuoka, JapanClinical Science Department, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanClinical Development Center, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanClinical Development Center, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanBiometrics Department, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanMedical Pharmacology Department, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanMedical Pharmacology Department, Development Division, Kyowa Kirin Co., Ltd., Tokyo, JapanLevodopa is the gold standard treatment for Parkinson’s disease. However, a high unmet medical need exists for longer-lasting oral levodopa formulations to achieve sustained motor improvement with reduced risk of the effect wearing off. In our previous non-clinical studies using rats, more than 3-fold prolongation of the levodopa half-life was achieved when it was combined with a high carbidopa dose. This study aimed to evaluate the effects of high-dose carbidopa on the pharmacokinetics of levodopa. A phase I study was performed to examine the effects of a combination of levodopa, carbidopa, and entacapone in healthy male volunteers. Levodopa and entacapone doses were set at approved dose levels. The carbidopa dose ranged from the approved 10 mg–600 mg. In addition to plasma concentrations of levodopa, those of the metabolites were also determined to evaluate their inhibitory effects on levodopa-metabolizing enzymes. The plasma concentrations of levodopa and its metabolites were monitored by liquid chromatography-tandem mass spectrometry up to 24 h after administration. The observed adverse effects were mild, and all participants completed the study. At higher carbidopa doses, the area under the levodopa plasma concentration-time curve increased by approximately 2-fold, and the half-life of levodopa was slightly prolonged by < 1.4-fold. These changes were much smaller than those observed in rats. The ratios of levodopa metabolites suggested that dopa deoxycarboxylase inhibition was saturated at a carbidopa dose of 300 mg. In conclusion, higher carbidopa doses are tolerable, and the effect of carbidopa on levodopa half-life is limited.Clinical trial registrationhttps://jrct.mhlw.go.jp/en-latest-detail/jRCT2051200104, registry number jRCT2051200104.https://www.frontiersin.org/articles/10.3389/fphar.2025.1596139/fullParkinson’s diseasephase I clinical trialhigh-dose carbidopa combinationlevodopa half-life prolongationcontinuous dopamine stimulation |
| spellingShingle | Akane Hayashi Atsushi Hosomi Shinsaku Kihara Masato Nishi Saori Torisawa Yoshiumi Ouchi Hidenori Takada Junichi Enokizono A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics Frontiers in Pharmacology Parkinson’s disease phase I clinical trial high-dose carbidopa combination levodopa half-life prolongation continuous dopamine stimulation |
| title | A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics |
| title_full | A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics |
| title_fullStr | A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics |
| title_full_unstemmed | A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics |
| title_short | A phase I study to evaluate the effect of high-dose carbidopa on levodopa pharmacokinetics |
| title_sort | phase i study to evaluate the effect of high dose carbidopa on levodopa pharmacokinetics |
| topic | Parkinson’s disease phase I clinical trial high-dose carbidopa combination levodopa half-life prolongation continuous dopamine stimulation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1596139/full |
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